Nociceptin is a seventeen amino acid neuropeptide that has been recently identified as a potent endogenous agonist of the opioid-like receptor NOP (previously termed ORL-1). The NOP receptor is a G-protein coupled receptor with 47% overall homology to the opioid receptors and 64% identical in transmembrane domains. In spite of this homology, classical opioid ligands have very low affinity for this receptor. Activation of the NOP receptor leads to inhibition of adenylyl cyclase activity and modulation of neuronal K+ and Ca+2 conductance. It is structurally related to the opioid peptides but does not activate opioid receptors.
Nociceptin and its receptor are widely expressed throughout the central nervous system. Thus, nociceptin is likely to participate in a broad range of physiological and behavioral functions. Reports in literature have implicated its role in cough (see, for example, McLeod et al, Pulmonary Pharmacology & Therapeutics (2002), 15, 213-216) as well as in pain, feeding, locomotor activity, alcohol abuse, urinary incontinence, anxiety, stress, cardiovascular functions, sleep disturbance, Parkinson's Disease and Alzheimer's Disease.
3-Substituted 8-azabicyclo-[3.2.1]octanes were disclosed in U.S. Pat. No. 6,262,066 B1, WO 95/04742, WO 97/48397, and WO 98/25924; 3-substituted 8-azabicyclo-[3.2.1]octan-3-ols were disclosed in U.S. Pat. No. 6,727,254 B2.